SI9520108A - New heterocyclic substituted imidazoloquinoxalinones, their preparation and their use - Google Patents

Abstract

Imidazoloquinoxalinones have the formula (I), in which R<1> stands for hydrogen, branched or linear C1-5-alkyl or a phenyl, pyridyl or thienyl group possibly substituted by one to two chlorine atoms, a trifluoromethyl, a nitrodioxy or a methylene dioxy group; R<2> stands for hydrogen, C1-5-alkyl or C3-8-dialkylaminoalkyl; R<3> stands for a chlorine or bromine atom, a trifluoromethyl, cyano or nitro group; A stands for a five-membered heterocycle with 1-4 nitrogen atoms or 1-2 nitrogen atoms and one oxygen or sulphur atom possible substituted by R<4> and R<5>; the radicals R<4> and R<5>, that may be the same or different, stand for hydrogen, C1-5-alkyl, C1-5-hydroxyethyl, phenyl, phenyl substituted by a chlorine atom, a trifluoromethyl or nitro group, -CHO, -COOH, -COO-C1-5-alkyl, -CH2-NR<6>R<7> (in which R<6> = H, C1-5-alkyl, R<7> = H, C1-5-alkyl), -CH2-NH-CO-R<8> (in which R<8> = C1-5-alkyl, phenyl, a phenyl group or an heteroaryl group possibly substituted by a chlorine atom of a nitro or trifluoromethyl group) or -CH2-NHCONHR<8>; and B stands for a bond or a C1-5-alkylene chain. Also disclosed are the tautomer and isomer forms of these compounds, as well as their physiologically compatible salts. These new substances have good glutamate antagonistic effects and are useful for controlling neurodegenerative diseases.

Description

BASF AKTIENGESELLSCHAFT

Novel heterocyclic substituted imidazolo-quinoxalinones, their preparation and use

DESCRIPTION

The present invention relates to novel heterocyclic substituted imidazolinoquinoxalinones, to methods for their preparation as well as to their use for disease control.

T.i. excitatory amino acids, such as e.g. glutamic acid, are very widespread in the central nervous system. These excitatory amino acids act as transmitters for glutamate receptors, of which we know different subtypes. One subtype is called e.g. by the specific N-methyl-D-aspartate agonist NMDAreceptor. This NMDA receptor has different binding sites for agonists or. antagonists. The amino acid glycine also binds at the NMDA receptor and modulates the effect of the natural glutamic acid agonist. Antagonists at this glycine binding site may then exhibit antagonistic effects at the NMDA receptor and inhibit this receptor hypersensitivity.

Two other subtypes of glutamate receptors are AMPA and kainate receptors, which are each designated by specific agonists 2-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) and kainic acids, respectively. Analogous to the NMDA receptor already indicated, antagonists of these receptors could also inhibit hypersensitivity.

Increased glutamate levels occur in a variety of neurodegenerative diseases or psychiatric disorders, which can lead to sensitization or toxic effects in the central nervous system.

Glutamant receptor subtype antagonists may therefore serve to treat these diseases. Glutamant antagonists, in particular NMDA antagonists or. their modulators (such as glycine antagonists) and AMPA antagonists are therefore suitable for therapeutic use as agents for neurodegenerative diseases (Chorea Huntington and Parkinson's disease), neurotoxic disorders after hypoxia, anoxia or ischemia, as occurring after stroke, or as antiepileptic drugs, antidepressants and anxiolytics (cf. Arzneim. Forschung 1990, 40, 511-514; TIPS, 1990, 11, 334-338, and Drugs of the Future 1989, 14 (11), 10591071).

The known type of imidazolo-quinoxalinones of formula II is:

II 'O.

Thus, DE-OS 3 004 750 and DE-OS 3 004 751 describe substances that have anti-allergic effects. Furthermore, imidazolo-quinoxalinones as phosphodiesterase inhibitors have been proposed for protection in US 5 166 344 (= EP 400583) as agents that affect cardiac blood circulation.

In the field of central nervous system (CNS), U.S. Patent No. 5 182 386 proposes the protection of imidazolo-quinoxalins, which are antagonists or inverse agonists of the GABA receptor and may be used to suppress anxiety, sleep disorders, convulsions and to improve memory.

Quinoxaline-2,3-dione derivatives have been extensively described as glutamate antagonists in many publications (e.g., EP 374 534 and EP 260 467).

Compounds heterocyclic substituted in the benzoid ring are e.g. subject matter WO 92/07847. Condensed heterocycles, including the imidazolo quinoxalinone system, are subject to US 5 153 196 and US 5 196 421 as well as to WO 93/20077. The latter also shows the substitution of heterocycles with 2-4 nitrogen atoms in the benzoid portion of the ring system.

Compounds published as glutamate antagonists are labeled in the annelated imidazole ring only with alkyl, trifluoromethyl or phenyl substituents.

It has been found that the substitution of imidazolo-quinoxalinone with heterocycles in the benzoid moiety and carboxylic acids or their esters in the annelated imidazole ring leads to new potent glutamate antagonists. They are therefore particularly suitable for the therapies of neurological disorders that can be affected.

The subject of the present invention are novel imidazolo-quinoxalinones of formula I

where

R ¹ means hydrogen, branched or straight-chain C ₁₅ -alkyl, or optionally with one to two chlorine atoms, a trifluoromethyl, nitro or methylenedioxy group substituted phenyl, pyridyl or thienyl group

R ² represents hydrogen, C ₅ alkyl or a C _ss -dialkilaminoalkil

R ³ represents a chlorine or bromine atom, a trifluoromethyl, cyano or nitro group

A represents a five-membered optionally substituted R ⁴ and R ⁵ heterocycle of 1-4 nitrogen atoms or 1-2 nitrogen atoms and an oxygen or sulfur atom, each of R ⁴ and R ⁵ being identical or different, represents hydrogen, C15-alkyl, C15-hydroxyethyl, phenyl, with a chlorine atom or a trifluoromethyl or nitro group substituted phenyl, -COOH, -COO-C1-C6-alkyl, -CH2-NR ⁶ R ⁷ (R ⁶ = H , C15 alkyl, R ⁷ = H, C ^ alkyl), -CH2-NH-CO-R ⁸ (R ⁸ = CFC _with alkyl, phenyl, optionally with a chlorine atom, a nitro or trifluoromethyl group, a substituted phenyl group or heteroaryl group) or -CH ₂ NHCONHR ⁸ and

B represents a bond or a C 1 -C 4 alkylene chain, as well as their tautomeric and isomeric forms and their physiologically tolerable salts.

Preferred compounds of formula I are those wherein R ¹ represents a methyl, ethyl or phenyl group. R ² represents preferably a methyl or ethyl group or a hydrogen atom. To the extent that R ² is hydrogen, the compounds are acids capable of forming salts with alkali and alkaline earth metal hydroxides or organic nitrogen bases. By the formation of salts, e.g. with sodium hydroxide or tris- (hydroxymethyl) methylamine, acids can be converted, if desired, to a water-soluble form. Preferred substituents for R ³ are electron-withdrawing agents such as e.g. nitro or trifluoromethyl group at position 7.

For the 5-membered heterocycles, pyrrole and its derivatives are preferred for A. Preferred pyrrole derivatives are 3-formylpyrrole, acyl derivatives of 3-aminomethylpyrrole, such as benzoyl or pyridoyl derivatives or those having an aryl urea group, with particular emphasis on the substitution of the benzoyl group with the nitro or CF ₃ group. As

The 5-ring system with 2 N atoms should preferably be referred to the imidazole system and its derivatives, as well as benzimidazole and pyrazole, and 5-ring heterocycles of 3 and 4 N atoms are e.g. 1,2,3-triazole and 1,2,4-triazole and their derivatives, as well as the tetrazole system.

B is preferably a bond.

The present heterocyclic substituted imidazolo-quinoxalinones have surprising advantages over the known imidazolo-quinoxalinones, in particular the higher efficiency.

The compounds of the present invention can be prepared in various ways.

8-amino-imidazolinoquinoxalinone of formula III h ₂ n

B-COOR ²

N

H

III 'O wherein R ¹ , R ³ and B have the meanings indicated above and R ² represents an alkyl group, reacted with 1,4-dicarbonyl compounds or succinic dialdehyde derivatives, or with cyclic or acyclic acetals derived from them, e.g. with the formula IV

IV into pyrroles.

The compounds of formula IV are readily available or can be prepared by conventional methods.

The conversion to the pyrrolyl compounds is carried out according to the usual procedures indicated e.g. in: C. Ferri, Reaktionen der organischen Synthese, Thieme Verlag 1978, p. 708 ff., Preferably in ice at 60-120 ° C. By using appropriately substituted diketones, respectively. of the acetals of formula IV can be prepared pyrrolyl compounds of the present invention.

^r1 COOR2

N '

H 'O

In the thus prepared pyrrolyl compounds, the substitution of R ⁴ or. R ^{5 is} modified appropriately. Thus, e.g. the aldehyde group is converted by reduction into a hydroxyalkyl group and by reductive amination to an aminoalkyl group.

The reductive amination is generally carried out at temperatures from 5 to 80 ° C, preferably from 10 to 30 ° C, in the presence of a reducing agent such as sodium cyanoborohydride or hydrogen in the presence of hydrogenation catalysts such as Pd / charcoal, Pt / charcoal or Raney nickel , preferably in polar organic solvents such as alcohols or dimethylformamide.

Aldehyde can be used by conventional processes such as e.g. described in: R.C. Larock,

Comprehensive Organic Transformations, 1989, VCH Publisher, p. 838 et seq., Is oxidized to the carboxylic acid of the invention; preferably oxidation is carried out with potassium permanganate in a solvent such as acetone at a temperature of 25 ° C.

The starting compounds of formula VI, wherein R ^{3 has} the above meaning, do not comprise a nitro group, but may be prepared analogously to the process in the sense of EP 400 583, followed by nitration and reduction of a nitro group according to scheme 1:

Scheme 1

R ³

vi ^Hal m ^Rl ^ B -COOR ² + ί = Ί

NO2

VII

B-COOR ²

B-COOR ²

B-COOR ²

III

It is known that halogen-substituted nitrobenzenes (VI) can be reacted with imidazoles VII which are unsubstituted at the nitrogen atom N _p in suitable solvents such as dimethyl sulfoxide, dimethylformamide or acetonitrile at temperatures between 0 and 140 ° C, and with the addition of bases, such as of potassium carbonate.

It is further known that the substitution of the halogen atom by 4- and 4,5-disubstituted imidazoles is such that a nucleophilic attack takes place at the least sterically hindered nitrogen atom of imidazole, so that in this case uniform products (VIII) are formed.

Ί

The reduction of nitro compounds to aniline derivatives IX can be carried out in a manner known per se, e.g. by catalytic hydrogenation with palladium or nickel as catalyst, or also with zinc II chloride.

o-halogen-nitrobenzenes of formula VI are commercially available or can be prepared by known methods.

With a double-activated carbon acid derivative such as phosgene, diphenylcarbonate or preferably Ν, Ν'-carbonyldiimidazole, in an inert aprotic solvent at an elevated temperature of 150 to 200 ° C, the ring is terminated into imidazolinoquinoxalinone X. Suitable solvents are decalin, tetralin, tetralin 2-Dichlorobenzene or 1,3-dimethylethylene or -propyleneurea. The process for the preparation of nitro compounds XI is characterized in that compounds X (R ³ is defined as above, except that the nitro group is not covered) are nitrated with nitric acid, a mixture of sulfuric acid and nitric acid or sulfuric acid-potassium nitrate at temperatures between -10 and 20 ° C.

Reduction of the nitro group as described above yields starting compounds III suitable for the preparation of pyrrolyl compounds V.

A further process for the preparation of the substances of the present invention is such that, in the manner described above, the nitro-benzene derivative XII having two interchangeable halogen atoms is first reacted with imidazole derivative VII into compounds VHIb and in the second reaction with N- by heterocycle XIII to the compounds XIV and after reduction of the nitro group cyclize the obtained compounds as described previously:

Hal Hal

R3 NO2

HN ^ <: N

XII

VII

R <B-COOR ² ₊ > = <

B-COOR ²

VHIb

R ⁴

VII Ib + HN ^ A ^

R ⁵

B-COOR ²

XIII

XIV

1. reduction 2. cyclization

-> - - ->

R ^x -R ⁵ , A and B have the meanings given above.

Suitable heterocycles of formula XIII are, in particular, compounds with a substituent NH-group and may be derived from N-heterocycles of imidazole, pyrazole, 1,2,3-triazole,

1,2,4-triazole and tetrazole. Suitable heterocycles, however, may also contain an additional heteroatom other than an oxygen or sulfur atom.

The process can optionally be formulated by reacting the corresponding nitrobenzene with two alternating halogen atoms and one protected amino group XV at the correct position for later cyclization, with the desired heterocycle XIII, then with the desired imidazole derivative VII in XVI, then however, after removal of the amino protecting group, the ring in XVII is carried out as previously described:

Scheme 3

Hal o ₂ n

Hal

R ⁴

NHCOCH3

Hal + VII NHCOCH 3

RS

XIII

R ⁴ .

r ?.

o ₂ n

NH ₂

XVII

A further process for the preparation of compounds I of the invention wherein R ³ represents a nitro group is such that compound XVIII ^{R 1} - .B-COOR ²

rr

XVIII is first nitrated in position 8 (XIX), then reduced to XX

R \

• B-COOR ²

R = NO ₂ (XIX) R = NH ₂ (XX) protecting the amino group, re-nitrated at position 7 and then releasing the appropriate o-aminonitro compound XX by removing the protecting group for further metabolism by e.g. furan derivatives IV.

B-COOR ²

XXI

Compounds of formula I in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A and B have the meanings given above can be converted by hydrolysis to acids of formula I wherein R ¹ , R ³ , R ⁴ , R ⁵ , A and B have the meanings given and R ² represents a hydrogen atom.

The hydrolysis takes place preferably under alkaline conditions, e.g. in the presence of an alkali metal hydroxide or sodium hydrogen carbonate, in a solvent such as water, lower alcohol, tetrahydrofuran or mixtures thereof. The organic acids thus obtained are optionally converted into physiologically acceptable amine or metal salts. This includes in particular alkali metal salts such as sodium and potassium, alkaline earth metals such as calcium, other metals such as aluminum, as well as organic base salts such as morpholine, piperidine, mono- and diethanolamine ah tris- (hydroxymethyl) aminomethane .

The compounds of the present invention are antagonists of the excitatory amino acid glutamate, in particular antagonists of the glycine binding site of the NMDAreceptor, AMPA receptor and kainate receptor.

They are suitable as active substances in human medicine and can be used for the preparation of drugs for the treatment of neurodegenerative disorders and neurotoxic disorders of the central nervous system, as well as for the preparation of spasmolytics, antiepileptics, anxiolytics and antidepressants.

The pharmacological efficacy of compounds I was investigated in the isolated membrane material of the rat large brain. For this purpose, the membranes were incubated with the radioactively labeled substances ³ H-2-amino-3-hydroxy-5methyl-4-isoxazolpropionic acid ( ³ H-AMPA), [ ³ H] -glycine or [ ³ H] in the presence of the compounds of the invention. -kainates that specifically bind to AMPA-, NMDA- or kainate receptors. Following this incubation, the extent of binding of said radioactive receptor ligands to membrane receptors was determined on the basis of radioactivity measured by scintillation counting. By the concentration-dependent repression of this binding to the compounds of the invention, the affinity of the compounds of the invention for the corresponding receptors can be calculated. The dissociation constant K _T (as an affinity criterion) was determined by iterative nonlinear regression analysis with a statistical analysis system (SAS) similar to the Ligand program of PJ Munson and D. Rodbard (Analytical Biochem. 107, 220 (1980), Ligand: Versatile Computerized Approach for Characterization of Ligand Binding Systems).

The following in vitro investigations were performed:

1. Binding of ³ H-2-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid ( ³ H-AMPA)

For preparation of the membrane material, freshly collected large rat brain was homogenized together with a 15-fold volume of buffer solution A of 30 mM a, a, α-Tris- (hydroxymethyl) -methylamine hydrochloride (TRIS-HC1) and 0.5 mM ethylenediamine- tetraacetic acids (EDTA) - pH 7.4 - with an UltraTurrax® mixer. The suspension was centrifuged for 20 minutes at 48,000 g. Following the determination of the supernatant, the sediment-containing membrane-containing membrane material was washed 3 times with suspension in buffer solution A, followed by centrifugation at 48,000 g each for 20 minutes. The membrane material was then suspended in 15 times the volume of buffer solution A and incubated at 37 ° C for 30 minutes. The protein material was then washed twice by centrifugation and suspension and frozen at -70 ° C until use.

For the binding assay, the thawed protein material was washed twice at 37 ° C by centrifugation at 48000 g (20 minutes) and then suspended in buffer solution B of 50 mM TRIS-HC1, 0.1 M potassium thiocyanate and 2.5 mM calcium chloride - pH 7.1. Subsequently, 0.25 mg of membrane material, 0.1 µg, Ci ³ H-AMPA (60 Ci / mmol) as well as compound I were dissolved in 1 ml of buffer solution B of solution B and incubated for 60 minutes on ice. The incubated solution was filtered through a CF / B filter (Whatman), which was treated with a 0.5% aqueous polyethyleneimine solution for at least 2 hours. The membrane residue was then washed with 5 ml of cold buffer solution B to separate bound and free ³ H-AMPA. After measuring the radioactivity of bound ³ H-AMPA in membrane material by scintillation counting, K _f values were determined by regression analysis

2. Binding of [ ³ H] -glycine

For membrane preparation for the ³ H-glycine binding assay, freshly removed rat hippocampi were homogenized in 10 times the volume of preparative buffer (50 mM Tris-HCl, 10 mM EDTA) with a Potter homogenizer. The homogenate was centrifuged for 20 minutes at 48,000 g. The supernatant was discarded and the membranes contained in the pellet were washed twice by resuspension and centrifugation at 48,000 g (20 minutes each). The resuspended membranes were frozen in liquid nitrogen and thawed again at 37 ° C. After rewashing, the membrane suspension was incubated at 37 ° C for 15 minutes in a shaking water bath. After 4 further rinsing steps (each 20 minutes centrifugation at 48000 g and resuspension in preparative buffer), the membranes were frozen until further use at -70 ° C.

The frozen membranes were thawed at 37 ° C and washed twice by centrifugation at 48000 xg (20 minutes) and then resuspended in binding buffer (50 mM Tris-HCl pH 7.4; 10 mM MgCl ₂ ). The incubation tube contained 0.25 mg of protein (membrane), 25 nM ³ H-glycine (16 Ci / mmol), and the substances to be tested in a total of 0.5 ml of binding buffer. Non-specific binding was determined by the addition of 1 mM glycine. After 60 minutes of incubation at 4 ° C, the bound and free ligand were separated from each other by filtration through GF / B-filters and subsequent washing with approx. 5 ml of ice-cold binding buffer. The residual radioactivity on the filters is determined by liquid scintillation counting. From dissipation curves, dissociation constants were calculated using the iterative nonlinear adaptation program or the corresponding Cheng and Prusoff equation.

3. Binding of [ ³ H] -kainates

For membrane preparation for the [ ³ H] -kainate binding assay, freshly removed large rat brain was homogenized in preparative buffer (30 mM TrisHCl pH 7.4, 0.5 mM EDTA) with an Ultra-Turraxa® mixer in 15x volume. The homogenate was centrifuged for 20 minutes at 48,000 g. The supernatant was discarded and the pellet-containing membranes were washed 3 times in total by resuspension in preparative buffer and by centrifugation at 48,000 g (20 minutes each). After the third washing step, the membranes were incubated at 37 ° C. The membranes were then washed twice by centrifugation and resuspension and frozen at -70 ° C until further use.

The frozen membranes were thawed at 37 ° C, suspended in binding buffer (50 mM Tris-HCl pH 7.4) and centrifuged for 20 minutes at 48000 g. The membranes contained in the pellet were resuspended in binding buffer. The incubation tube contained 0.25 mg of protein (membrane), 0.058 μθ (58 Ci / mmol) as well as the substances to be tested in a total of 1 ml of binding buffer. Non-specific binding was determined in the presence of 0.1 mM glutamate. After incubation on ice for 60 minutes, the bound and free ligand were separated from each other by filtration through CF / B-filters and subsequent washing with 5 ml of ice-cold binding buffer. CF / B filters were treated with 0.5% polyethyleneimine for at least 2 hours earlier. Evaluation of the lowering curves the calculation of dissociation constants was performed with a nonlinear adjustment program or correspondingly to the Cheng and Prusoff equations.

These tests showed very good effects of the compounds.

The medicaments of the invention contain, in addition to conventional drug excipients, a therapeutically effective amount of compounds I. For topical external use, e.g. in powders and ointments, the active substances may be at their usual concentrations. Generally, the active ingredients are in an amount of 0.0001 to 1% by weight, preferably 0.001 to 0.1% by weight.

For internal use, the preparations are given in single doses. In each dose, 0.1 to 100 mg per kg body weight is administered. The preparations can be administered daily in one or more dosages according to the type and severity of the disease.

The medicaments of the invention, in addition to the active ingredient carrier and diluent, are suitably desired in the application type desired. Pharmaceutical-technical auxiliaries, such as ethanol, isopropanol, oxetylated castor oil, oxetylated hydrated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, paraffin, and paraffin, can be used for topical external use. For internal use, for example, milk sugar, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.

They may further contain antioxidant agents such as tocopherol and butylated hydroxyanisole as well as butylated hydroxytoluene, flavor enhancers, stabilizing, emulsifying and gliding agents.

The substances contained in the preparation in addition to the active substance, as well as in the preparation of the pharmaceutical preparations, the substances used are toxicologically safe and transferable to the active substance concerned. Medicinal preparations are prepared in a conventional manner, e.g. by mixing the active ingredients with other conventional carriers and diluents.

Medicinal preparations can be administered in a variety of administration routes, such as oral, parenteral, subcutaneous, intraperitoneal and topical. Thus, formulations such as tablets, emulsions, infusion and injection solutions, pastes, ointments, gels, creams, lotions, powders and sprays are possible.

Implementing examples:

EXAMPLE 1

4,5-Dihydro-1-methyl-8- (pyrrol-1-yl) -7-trifluoromethyl-4-oxoimidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

a) 1- (2-Nitro-4-trifluoromethylphenyl) -4-carboxy-5-methylimidazole

Mixture of 10.45 g (0.05 mol) of 2-fluoro-4-trifluoromethyl-nitrobenzene, 7.7 g (0.05 mol of 4 (5) -carbethoxy-5 (4) -methylimidazole and 13.8 g of potassium carbonate heated in 100 ml of acetonitrile for 4 hours while stirring at reflux.

The cooled reaction mixture was mixed with 1000 ml of water, extracted with 250 ml of methylene chloride and the methylene chloride phase dried with magnesium sulfate. The dried solution was evaporated and the residue was triturated with ether to crystallize.

Yield: 11.4 g (66% of theory)

M.p .: 142-144 ° C.

b) 1- (2-amino-4-trifluoromethylphenyl) -4-carboxy-5-methylimidazole

11.6 g (0.034 mol) of the previously described compounds a) were hydrogenated with 2 g of Pd / charcoal catalyst (10% Pd) in 100 ml of ethanol at room temperature at atmospheric pressure. After the uptake of hydrogen is complete, the solution, which is removed from the catalyst, is evaporated in vacuo and the residue is crystallized with some ether.

Yield: 9.8 g (93% of theory)

M.p .: 189-190 ° C.

c) 4,5-Dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

7.3 g (0.0233 mol) of the previously described compound b) was heated with 4.2 g (0.0259 mol)

Ν, Ν′-carbonyldiimidazole in 100 ml of 1,2-dichlorobenzene 2.5 h with stirring under boiling. After cooling, the solid was removed and washed with acetone-ether.

Yield: 5.1 g (64.5% of theory).

M.p .: 270-271 ° C.

d) 4,5-Dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

5.0 g (0.015 mol) of the previously described compound c) is nitrated with a mixture of 50 ml of concentrated sulfuric acid and 50 ml of nitric acid (d = 1.50) for 72 hours at room temperature and then for another 1 hour at 60 ° C. Apply the nozzle after cooling to ice, suction and wash the product with water.

Yield: 3.9 g (70% of theory).

M.p .: 284-286 ° C.

e) 8-Amino-4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ester g (0.031 mol) previously described compounds d) dissolved in 200 ml of glacial acetic acid and then 15 g of powdered iron are added portionwise over 15 minutes. After 30 minutes, the precipitated precipitate was filtered off with suction and washed with acetic acid, water and methanol.

Yield: 10 g (91% of theory),.

M.p .: 300 ° C.

f) 1.5 g (0.0042 mol) of the previously described compound e) is taken up in 30 ml of ice, mixed with 1.12 g (0.085 mol) of 2,5-dimethoxytetrahydrofuran and quickly heated in a preheated oil bath to boiling point to dissolve. After 5 minutes, cool rapidly, suction the precipitate and wash with acetic acid and ether.

Yield: 0.75 g (44% of theory)

M.p .: 290-295 ° C.

c ₁₉ h ₁₅ f ₃ n ₄ o ₃

Analogously to process lf, the following 2.5 dimethoxytetrahydrofuran derivatives substituted at position 3 were prepared using the following compound.

2,5-dimethoxyfuran derivatives:

The compounds obtained from these are shown in Table I:

EXAMPLE 9:

4.5-Dihydro-8- (2,5-dimethylpyrrol-1-yl) -1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

1.0 g (0.0028 mol) of the compound of the example is only heated together with 2 g of acetonylacetone in 25 ml of acetic acid while boiling, all dissolving after 5 minutes. It is then heated for a further 10 minutes, cooled, the precipitated residue is filtered off with suction, washed with ether and dried in vacuo.

Yield: 0.9 g (75% of theory)

Mp .:> 300 ° C ^ 21 ^ 19 ^ 3 ^ 4 ^ 3

EXAMPLE 10

4.5-Dihydro-1-methyl-8- (pyrrol-1-yl) -7-trifluoromethyl-4-oxo-imidazolo [1,2-quinoxaline-2-carboxylic acid

Dissolve 0,5 g of the ester prepared in Example 1f in a solution of 1 g of LiOH in 50 ml of water with brief heating at 80 ° C. After a few hours, acidify with acetic acid at pH 5, suction the precipitate and dry in vacuo.

Yield: 0.4 g (86% of theory)

Mp .:> 300 ° C ^ 21 ^ 19 ^ 3 ^ 4 θ3

The following compounds are obtained in an analogous manner from the esters of Examples 2-9:

Tal. U o o o m Λ > 300 ° C cO rH i Mr Rücker > 0 »H (h Ή i Oh 2 m tii cd cd SC CD cd Oh o <*> cn cd K and d U Structural formula a o o \ _a o 7 ~ (j — z. aa / w R- o \ ° a o o o \ _a P iv / / ² \ / ^{S 33} O f o Example no. 11 12 1

• r—. £ o o o o ro Λ a 0 o o ro Λ formula that o M * Oh > 2 n vo 2 <* » Ph k • H i X and nj U t-H w tn m U « 2 Q in Oh o Oh o I \ in O \ ~ Oh 1 cs 2 lU iH s Λ / l— s a κ \ / Γ \ ) - 2 2 2 \ / / = \ C D W Mr Rücker y «J rH 1 r ' 2 \ <*> JU ^s In ^s f \ n _E3 \ JJl " <2 o o Strukt • -P > n c ! <H rH

20. 4,5-Dihydro-8- (imidazol-1-yl) -1-methyl-7-trifluoromethyl) -4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

a) 1- (5-Chloro-2-nitro-4-trifluoromethyl-phenyl) -4-carboxy-5-methylimidazole prepared according to example la from 2,4-dichloro-5-nitro-benzotrifluoride, and

4 (5) -carbethoxy-5 (4) -methylimidazole

M.p .: 118-119 ° C

C ₁₄ H _n ClF ₃ N ₃ O ₄

b) 4- (4-Carboxy-5-methylimidazol-1-yl) -2- (imidazol-1-yl) 5-nitro-benzotrifluoride g (0.013 mol) of the product prepared according to Example 1a is heated by

1.8 g (0.026 mol) of imidazole in 100 ml of acetonitrile for 120 h at reflux. The solvent was then distilled off, the residue was treated with ethyl acetate and water, the separate solvent phase was then washed again with water, dried and evaporated. After crushing the residue with diisopropylether, THF (99: 1 mixture) crystallizes the product.

Melting point: 160-162 ° C c ₁₇ h ₁₄ f ₃ n ₅ o ₄

c) 2- (4-Carboxy-5-methylimidazol-1-yl) -4- (imidazol-1-yl) -5trifluoromethyl-aniline

3.5 g of the product of Example 1b were heated in 50 ml of acetic acid until boiling and then 5.6 g of powdered iron was added portionwise. After 20 minutes, the solution was evaporated, the solution was evaporated in vacuo, water was added and extracted twice with ethyl acetate. The extract was then washed with the soda solution to make it acid-free, the solution was dried, evaporated and the residue was digested with ether.

Yield: 1.8 g (55% of theory)

M.p .: 265-266 ° C.

d) Preparation of the final product

0.7 g (0.002 mol) of the compound obtained after 20c is heated with 0.5 g of 1,1'27 carbonyl diimidazole in 50 ml of 1,2-dichlorobenzene for 2 hours at reflux. The precipitate obtained after cooling was filtered off with suction and washed with a hot methanol-isopropanol mixture.

Yield: 0.2 g (25% of theory)

Melting point: 265-270 ° C c ₁₈ h ₁₄ f ₃ n ₅ o ₃

Using the other starting compounds in an analogous manner, we prepare:

21. 4,5-Dihydro-1-methyl-8- (2-methylimidazol (1-yl) -7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid-ethyl ester)

Mp .:> 300 ° C ^ 19 ^ 15 ^ 3 ^ 4 ^ 3

22. 4,5-Dihydro-1-methyl-8- (1,2,4-triazol-1-yl) -7-trifluoromethyl-4-oxoimidazolo [1,2-a] quinoxaline-2-carboxylic acid-ethyl ester

Mp .: 291-293 ° CC _1? H ₁₃ F ₃ N ₆ O ₃

By saponification with lithium hydroxide, analogous to Example 10, the following compounds are obtained from the compounds of Examples 19-21:

23. 4,5-Dihydro-8- (imidazol-1-yl) -1-methyl-7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

M.p .: 291-293 ° C ^ 17 ^ 13 ^ 3 ^ 6 ^ 3

24. 4,5-Dihydro-1-methyl-8- (2-methyl) imidazol-1-yl) -7-trifluoromethyl-4-oxoimidazolo [1,2-a] quinoxaline-2-carboxylic acid

Melting point:> 300 ° C c ₁₇ h ₁₂ f ₃ n ₅ o ₃

25. 4,5-Dihydro-1-methyl-8- (1,2,4-triazol-1-yl) -7-trifluoromethyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

Melting point:> 300 ° C ^c 17h ₁₂ f ₃ n ₅ o ₃

26. 4,5-Dihydro-1-ethyl-8- (imidazol-1-yl) -7-trifluoromethyl-4-oxoimidazolo [1,2-a] quinoxaline-2-carboxylic acid

Melting point:> 300 ° C c ₁₇ h ₁₂ f ₃ n ₅ o ₃

27. 4,5-Dihydro-8- (3-formylpyrrol-1-yl) -1-methyl-7-nitro-4-oxoimidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester.

a) Preparation of starting material: 4,5-Dihydro-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester is prepared by the metabolism of 2-fluoronitrobenzene with 4 (5) carboxy-5 (4) methylimidazole, followed by hydrogenation and then ring ringing with N, N'-carbonyldimidazole.

b) 4,5-dihydro-1-methyl-8-nitro-4-oxo-imidazolo [1,2-a] quinoxaline 2-carboxylic acid ethyl ester g (0.09 mol) of the substance described previously under a), is added in portions at 0-5 ° C in 300 ml of 100% nitric acid with stirring. After 15 minutes, place the nozzle on ice, suction off and treat the residue with acetone to give the product in crystalline form.

Yield: 26 g (82% theory)

Melting point:> 300 ° C c ₁₄ h ₁₂ n ₄ o ₅

c) 4,5-Dihydro-8-acetamino-1-methyl-4-oxo-imidazolo [1,2-a] quinoxaline2-carboxylic acid ethyl ester

The compound previously described under b) is reduced with ferrous iron in boiling acetic acid.

Yield: 66% of theory.

Melting point:> 300 ° C c ₁₆ h ₁₆ n ₄ ° ₄

d) 4,5-Dihydro-8-acetamino-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester g of the compound described under d) is nitrated as follows, they were added portionwise in 25 ml of 100% nitric acid at 20 ° C and then stirred for a further 5 minutes.

Yield: 0.8 g (70% of theory)

Melting point:> 300 ° C c ₁₆ h ₁₅ n ₅ o ₆

e) 4,5-Dihydro-8-amino-1-methyl-7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

The former compound d) is hydrolysed selectively with hydrochloric acid, the compound being first heated to 70 ° C and then slowly cooled to room temperature.

Yield: 1.4 g (35% theory)

Melting point:> 300 ° C c ₁₄ h ₁₃ n ₅ o ₅

f) Preparation of the final product

1.0 g (0.003 mol) of the compound obtained by e) is reacted with 1.0 g of 2,5-dimethoxy-3-formyl-tetrahydrofuran in boiling ice according to Example 1f.

Yield: 0.3 g (24% of theory)

M.p .: 220-225 ° C

28. 4,5-Dihydro-1-methyl-8 - [(2-methyl) -imidazol-1-yl] -7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

a) 5-acetamino-4-fluoro-2- (2-methylimidazol-1-yl) -nitrobenzene (0.0138 mol) 5-acetamino-2,4-difluoro-1-nitro-benzene was reacted with 1.1 g (0.0135 mol) of 2-methylimidazole and 5 g of potassium carbonate in 50 ml of acetonitrile for 72 hours at 50 ° C with stirring. For treatment, the aspirated reaction mixture was evaporated in vacuo and purified by column chromatography (silica gel, methylene chloride + 5% methanol).

Yield: 1.0 g (26% of theory)

Melting point: 209-210 ° C (from isopropanol)

C ₁₂ H _n FN ₄ O ₃

b) 5-amino-2- (2-methylimidazol (1-yl) -4 - [(4-carboxy-5-methyl) (imidazol-1-yl)] - nitrobenzene

6.0 g (0.022 mol) of the compound described in a) is reacted with 3.4 g (0.022 mol) of 4 (5) -carbethoxy-5 (4) -methylimidazole and 6 g of potassium carbonate in 100 ml of DMF in 2 hours at 120 ° C with stirring. For treatment, the reaction solution is sucked off and evaporated in vacuo, water is added and extracted with methylene chloride. The residue obtained after drying and evaporation was recrystallized from isopropanol (yield: 3.5 g = 39%) and then stirred with 100 ml of hydrochloric acid at 60 ° C for 4 hours. For treatment, the hydrochloric acid is largely distilled off in vacuo, the product is neutralized with dilute ammonia at 0 ° C and extracted with methylene chloride. The residue was purified by column chromatography.

Yield: 1 g

c) 1.0 g of the compound described in b) is reacted by mixing with 0.6 g of N, N'carbonyldiimidazole in 50 ml of 1,2-dichlorobenzene for 2 hours at 160-170 ° C. After cooling to 50 ° C, decant the solution from the precipitate, treat the residue with hot acetone and suction off. Evaporated filtrate gave 0.1 g of the desired compound.

M.p .: 265-270 ° C c ₁₈ h ₁₆ n ₆ o ₅

29. 4,5-Dihydro-1-methyl-8- (imidazol-1-yl) -7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid ethyl ester

a) 5-amino-4-fluoro-2- (imidazol-1-yl) -nitrobenzene g (0.068 mol) of 5-amino-2,4-difluoronitrobenzene was added slowly at 0 ° C to a solution of 4.7 g of imidazole (0.069 mol), 2.1 g of sodium hydride (80% in oil; 0.07 mol) and then stirred at this temperature for several hours. It is then diluted with water and extracted several times with methylene chloride. After drying and evaporation, the isopropanol residue is recrystallized.

Yield: 7.1 g (45% of theory)

M.p .: 211-212 ° C.

b) 5-amino-2- (imidazol-1-yl) -4 - [(4-carboxy-5-methyl- (imidazol-1-yl)] nitrobenzene

4.2 g (0.027 mol) of 4 (5) -carbethoxy-5 (4) -methyl-imidazole were pretreated in 30 ml of DMF with 0.82 g of sodium hydride (80% in oil; 0.027 mol) for 1 hour and then added 6.1 g (0.027 mol) of the compound previously described in a) was stirred overnight. Before treatment, heat for another 1 hour at 50 ° C. For treatment, they are mixed with water, 3 ml of acetic acid are added, extracted with methylene chloride, dried and evaporated. Treatment with ether / isopropanol (95 + 5) gave the crystalline compound.

Yield: 4.2 g (42% of theory)

M.p .: 213-215 ° C.

c) Preparation of the final product

1.0 g of the compound described in b) is reacted as described in Example 28c to give 0.3 g (24% of theory) of the compound in accordance with this example.

M.p .: 328-330 ° C ^ 18 ^ 13 ^ 5θ6

Hydrolysis of the compounds of Examples 28 and 29 with lithium hydroxide according to Example 10 yields:

30. 4,5-Dihydro-1-methyl-8- (imidazol-1-yl) -7-nitro-4-oxo-imidazolo [1,2-a] quinoxaline-2-carboxylic acid

Melting point:> 300 ° C c ₁₅ h ₁₀ n ₆ o ₅

31. 4,5-Dihydro-1-methyl-8- (2-methylimidazol-1-yl) -7-nitro-4-oxoimidazolo [1,2-quinoxaline-2-carboxylic acid

Melting point:> 300 ° C c ₁₆ h ₁₂ n ₆ ° ₅

32. 4,5-Dihydro-8- (3-formylpyrrol-1-yl) -1-methyl) -7-nitro-4-oxoimidazolo [1,2-a] quinoxaline-2-carboxylic acid

Hydrolysis of the compound of Example 27 with lithium hydroxide in the sense of Example 10 yields the above compound.

Claims (5)

PATENT APPLICATIONS 1. Imidazolo-quinoxalinones of formula I H B-COOR ² where R ¹ means hydrogen, branched or linear _5- alkyl, or optionally with one to two chlorine atoms, a trifluoromethyl, nitro or methylenedioxy group substituted phenyl, pyridyl or thienyl group R ² represents hydrogen, C ₁₅ -alkyl or C ₃ -glycalkylaminoalkyl R ³ represents a chlorine or bromine atom, a trifluoromethyl, cyano or nitro group A represents a five-membered optionally substituted R ⁴ and R ⁵ heterocycle of 1-4 nitrogen atoms or 1-2 nitrogen atoms and an oxygen or sulfur atom, each of R ⁴ and R ⁵ being identical or different, represents hydrogen, C ₁₅ -alkyl, _5- hydroxyethyl, phenyl, chlorine atom or trifluoromethyl or nitro group substituted phenyl, -CHO, -COOH, -COO-C ₅ -alkyl, -CH ₂ -NR ⁶ R ⁷ (R ^{6 as the} case may be substituted by a chlorine atom, a nitro or trifluoromethyl group a phenyl group or a heteroaryl group) or -CH ₂ NHCONHR ⁸ and B represents a bond or a C ₁ -C ₅ alkylene chain, as well as their tautomeric and isomeric forms and their physiologically tolerable salts. Imidazolo-quinoxalinones of formula I according to claim 1 for use in the control of diseases. Use of the imidazolo-quinoxalinones of the formula I according to claim 1 for the preparation of medicaments for the suppression of neurodegenerative disorders, neurotoxic disorders of the central nervous system, in particular stroke, traumatic brain and spinal cord lesions, as well as epilepsy, states of anxiety and depression. Medicinal preparations for oral, parenteral and intraperitoneal use, characterized in that they contain, in addition to conventional drug excipients, 0.1 to 100 mg / kg body weight of at least one imidazolo-quinoxalinone I according to claim 1. Medicinal preparations for intravenous use, characterized in that they contain, in addition to the usual drug excipients, 0.001 to 10% by weight. % of at least one imidazolinoquinoxalinone I according to claim 1.